1. Field of the Invention
This invention relates to a method for improving non-invasive determination of the concentration of an analyte in a human tissue, and, more particularly, a method for improving non-invasive determination of the concentration of analytes in human tissues and human body parts by applying a coupling agent at the interface between an optical measurement device and the surface of a tissue of a human.
2. Discussion of the Art
Non-invasive determination of the concentration of an analyte in a biological sample, e.g., glucose in human tissue, has been attempted by several methods. Optical methods employing infrared radiation operate on the basis that light can penetrate the tissue and then provide an absorption or scattering measurement. These methods involve the steps of introducing light and collecting light by means of optical devices having elements in contact with the skin.
Robinson et al., U.S. Pat. No. 4,975,581, describes a method for the non-invasive measurement of the concentration of glucose by detecting diffusely reflected light having a wavelength in the near infrared region of the electromagnetic spectrum. Barnes et al., U.S. Pat. No. 5,379,764, describes a method for the non-invasive measurement of the concentration of glucose via light having a wavelength in the near infrared region of the electromagnetic spectrum. The interface between the optical measurement device and the surface of the skin is formed by contacting the surface of the skin with the optical measurement device. Dahne et al., U.S. Pat. No. 4,655,225, describes an optical system for in vivo measurement of the concentration of glucose. In this system, light is transmitted from an optical element to the skin and from the skin to the optical element through the air. Caro, U.S. Pat. No. 5,348,003, describes the use of temporarily modulated electromagnetic energy for the measurement of the concentration of glucose and other analytes, but a portion of the light energy is propagated through the air to the surface of the skin and reflected back from the skin.
Marbach, xe2x80x9cMeasurement Techniques for IR Spectroscopic Blood Glucose Determinationxe2x80x9d, published in 1993, and R. Marbach, T. H. Koschinsky, F. A. Gries, and H. M. Heise, xe2x80x9cNoninvasive Blood Glucose Assay by Near-infrared Diffuse Reflectance Spectroscopy of the Human Inner Lipxe2x80x9d, APPLIED SPECTROSCOPY, Vol. 47, 1993, pp. 875-881, describe an optical accessory for carrying out measurements of diffuse reflectance on a human lip. That accessory suppresses the insensitivity to Fresnel or specular reflection on the skin surface area by matching the refractive index of the optical accessory to that of tissue. Calcium fluoride (CaF2) was disclosed as the material for constructing the optical accessory. Calcium fluoride is not an ideal index match to tissue, having an index of 1.42, relative to that of tissue, at approximately 1.38. Thus, an index mismatch occurs at the accessory to tissue interface assuming complete contact between the accessory and the tissue. The optical efficiency of the accessory is further compromised by the fact that the accessory and the tissue will not make perfect optical contact due to roughness of the surface of the tissue. The result is a significant refractive index mismatch where light is forced to travel from the accessory (refractive index=1.42) to air (refractive index=1.0) and then to tissue (refractive index=1.38). Thus, the inherent roughness of tissue results in small air gaps between the accessory and the tissue, which decrease the optical throughput of the system, and subsequently compromise the performance of the measurement accessory.
Simonsen et al., U.S. Pat. No. 5,551,422, describes a method for the determination of the scattering coefficient in tissue based on spatially resolved diffuse reflectance. A clinical apparatus and a method based on this patent employ a double-stick tape to affix the optical probe to the surface of the skin. This interface material is used for mechanical attachment purpose and does not address problems relating to measurement variations. J. T. Bruulsema, et al, xe2x80x9cCorrelation between blood glucose concentration in diabetics and noninvasively measured tissue optical scattering coefficientxe2x80x9d, OPTICS LETTERS, Vol. 22, 1997, pp.190-192 (hereinafter xe2x80x9cBruulsema, et al.xe2x80x9d), describe a clinical study based on the method of Simonsen et al., U.S. Pat. No. 5,551,422. Another clinical study was reported by L. Heinemann, et al., xe2x80x9cNon-invasive continuous glucose monitoring in Type I diabetic patients with optical glucose sensorsxe2x80x9d, Diabetologia, Vol. 41, 1998, pp. 848-854. In both studies significant drift in the optical measurement was observed, leading to changes in the scattering coefficient independent of changes in glucose concentration and lack of correlation between changes in the scattering coefficient and changes in glucose concentration. The poor quality of the data did not allow the use of statistical analysis to correlate or predict the concentration of glucose.
The use of optical coupling agents for improving contrast and image quality in microscopic examinations is known in the art. In a classical example, immersion oil has been applied to the interface between a microscope lens and the sample object. The use of optical matching fluids to improve the precision of optical measurements is also known in the art. The use of an optical matching fluid that has the same refractive index as that of the object to be measured decreases reflection losses at the surface and improves measurement precision and accuracy.
Chance, U.S. Pat. No. 5,596,987 and Chance, U.S. Pat. No. 5,402,778, describe methods for measuring optical properties of tissue. In particular, U.S. Pat. No. 5,596,987 discloses a spectrophotometric system including a spectrophotometer with an optical input port adapted to introduce radiation into an object and an optical detection port adapted to detect radiation that has migrated through a path in the object, photon escape preventing means arranged around the object, which is relatively small, and adapted to limit escape of the introduced photons outside the object, and processing means adapted to determine an optical property of the object based on the changes between the introduced and the detected radiation. The system also includes an optical medium of a relatively large volume, forming photon escape preventing means, having selectable scattering and absorptive properties, positioning means adapted to locate the biological tissue of interest into the migration path to create a tissue-medium optical path, the optical medium substantially limiting escape of photons from the tissue-medium optical path, and processing means adapted to determine a physiological property of the tissue based on the detected optical property of the tissue-medium optical path and the scattering or absorptive properties of the optical medium. The photon escape preventing means includes an optical medium of a selectable optical property surrounding the object. The selectable optical property is an absorption or scattering coefficient. The medium has at least one optical property matched to the optical property of the object. The optical coupling system includes an optical matching fluid that is contained within a flexible, optically transparent bag and disposed partially around the monitored tissue and the excitation and detection ports of the system. The optical medium may include scattering material, such as solid particles having smooth, spherical surfaces, or styrofoam. The optical medium may include a liquid having selectable absorptive or scattering properties, such as an Intralipid solution. The optical coupling medium may include a pliable solid having selectable scattering or absorption properties. The spectrophotometric system employing such an optical medium allows one to locate tumors having optical properties different from those of normal tissue.
Messerschmidt, U.S. Pat. Nos. 5,655,530 and 5,823,951, describes an optical method for measuring a blood analyte in human tissue non-invasively. Specifically, these patents disclose disposing an index-matching medium between a sensor element and a sample area on a skin surface. The method of measurement described in these patents requires detecting a mixture of diffuse and specular reflection. The use of an index-matching medium decreases the specular reflection component that is attributable to Fresnel reflections at glass/air/tissue interfaces. Two types of index-matching media were described, hydrophobic refractive index matching fluids and hydrophobic refractive index matching fluids containing a hydrophilic additive.
Co-pending U.S. application Ser. No. 09/080,470, filed May 18, 1998, assigned to the assignee of this application, describes a non-invasive glucose sensor employing a temperature control. One purpose of controlling the temperature is to minimize the effect of physiological variables. Co-pending U.S. application Ser. No. 09/098,049, filed Nov. 23, 1998, assigned to the assignee of this application, describes methods for determining optical properties of tissue having more than one layer. The methods involve the use of a plurality of groups of closely spaced optical fibers that are located at spatially resolved measurement sites. Each group yields information relating to a specific layer in the sample. The selection of a particular layer for which the optical property is determined depends on the distance between the light illumination site and the site of the group of detecting elements. The layers described in the co-pending application are within the depth of 3 mm for samples of human tissue. In body parts having a thin layer of skin, such as the forearm or the abdomen, this depth encompasses the stratum corneum, the epidermis, and the dermis. Both applications teach the use of a temperature controlled optical element that is brought in contact with the skin.
Although a variety of spectroscopic techniques have been disclosed in the art, there is still no commercially available device that provides non-invasive measurements of glucose concentration with an accuracy that is comparable to that of invasive methods, i.e., analysis of glucose in blood withdrawn from human body parts. Also, spectroscopic techniques in the prior art fail to address the effect of variations in efficiency of optical coupling between the measuring device and the skin. These variations result in drift of the measurement induced by the measuring device. As a result, current approaches to non-invasive metabolite testing, such as glucose monitoring, have not achieved acceptable precision and accuracy.
Calibration of an optical instrument for non-invasive glucose measurements can be achieved by performing a meal tolerance test or an oral glucose tolerance test. A test subject ingests a given amount of food or drink after fasting for several hours. As a result of such ingestion, the glucose concentration in the blood of the test subject will change. The concentration of glucose in blood can be determined by a conventional prior art invasive procedure, such as that involving collection of blood by means of a finger stick and determination of blood glucose level via a disposable test strip and an optical or electrochemical detector. The signal from the non-invasive optical instrument is processed and is correlated with the glucose concentration determined at the same time by the invasive procedure. The resultant plot of data collected by means of the non-invasive procedure vs. data collected by means of the invasive procedure is a calibration curve, which can be obtained by the use of any appropriate fitting method, such as linear least squares fitting.
Touching the optical measuring probe to the skin leads to a unidirectional change in signal as a function of time, even in the absence of changes in glucose concentration. The temporal behavior reported by J. T. Bruulsema, et al. provided an example of such variations. This change in signal as a function of time, independent of changes in concentration of analytes in the sample, is called drift.
Robinson, et al. (U.S. Pat. No. 4,975,581) observed such a drift and used the first derivative of the spectrum to minimize it. This compensation, however, does not address the cause of the problem. In fact, in the spatially resolved diffuse reflectance measurement at the skin, drift of signal observed by Bruulsema, et al. was so large that it precluded statistical analysis of the results.
In one aspect, this invention provides a method for determining the concentration of an analyte in a biological sample comprising the steps of:
(1) providing an optical measuring instrument that comprises at least one thermally controllable optical measuring element that comes into contact with the surface of the biological sample;
(2) applying an inert, thermally conductive, optically transparent coupling agent to the at least one optical measuring element or to the surface of the biological sample or both so that the coupling agent will be disposed at the interface of the surface of the biological sample and the at least one optical measuring element;
(3) measuring optical properties of the biological sample by means of the at least one optical measuring instrument; and
(4) correlating the optical properties of the biological sample with the concentration of an analyte in the biological sample.
In another aspect, this invention provides a method for calibrating an optical instrument for a non-invasive optical measurement from a tissue of a body part comprising the steps of:
(1) providing an optical measuring instrument that comprises at least one thermally controllable optical measuring element that comes into contact with the surface of the tissue;
(2) applying an inert, thermally conductive, optically transparent coupling agent to the at least one optical measuring element or to the surface of the tissue or both so that the coupling agent will be disposed at the interface of the surface of the tissue and the at least one optical measuring element;
(3) inducing a change in the concentration of the analyte in the tissue over a defined period of time;
(4) measuring the change in at least one optical property of the tissue by means of the at least one optical measuring element during the defined period of time;
(5) determining the change in the concentration of the analyte in the tissue by means of a reference method that involves taking a sample from the tissue for analysis during the defined period of time;
(6) correlating the change in the at least one optical property of the tissue with the change in the concentration of the analyte in the tissue to derive calibration data; and
(7) using the calibration data to determine the concentration of the analyte in the tissue.
A coupling agent suitable for this invention must have several properties to enable it to help decrease measurement variation, especially drift. One of the most important properties is sufficiently high optical stability that the optical properties of the coupling agent do not change even during prolonged experiments, such as meal tolerance tests and oral glucose tolerance tests, which tests typically extend over a period of several hours. The optical properties of the coupling agent should also remain stable during storage. Thus, hygroscopic agents, such as glycerol, are not suitable as coupling agents for this invention, because they absorb water from the biological sample, e.g., human tissue, and the atmosphere, which causes their physical properties to change over time.
Secondly, the coupling agent should have sufficiently high thermal conductivity to allow fast, efficient heat transfer between the optical probe and the biological sample, e.g., human tissue. The thermal conductivity of the coupling agent should be at least four times that of air, i.e., greater than 1 miliwatt/cm/xc2x0 C.
Third, the coupling agent should have sufficiently high viscosity to prevent it from migrating from the measurement area. Yet, it should also have sufficiently low viscosity to allow sufficient contact between the optical probe and the biological sample, e.g., human tissue, and to permeate into any small pockets between the probe and the biological sample that would otherwise be filled with the air. The preferred viscosity of the coupling agent ranges from about 10 centipoises to about 100,000 centipoises.
Fourth, the coupling agent should be inert. Material from the coupling agent should not diffuse into the biological sample and material from the biological sample should not diffuse into the coupling agent. Thus, coupling agents containing a high concentration of water or alcohol are not suitable for this invention. Low molecular weight compounds, such as water or alcohol, can diffuse through the biological sample during the period of measurement, thereby causing a change in the optical properties of the biological sample and also a change in the composition of the coupling agent and, consequently, the physical properties of the coupling agent, such as its refractive index or its thermal conductivity. Coupling agents containing water and/or alcohol may extract materials such as salt and proteins from the tissue over a period of time. As a result, the properties of both the biological sample and the coupling agents may vary, and may contribute to changes in the signal over a period of time, i.e., drift.
The use of an appropriate coupling agent results in decreasing background variations in an optical measurement designed to determine the concentration of an analyte in a biological sample, including human tissue, such as the skin. The method of this invention results in decreasing drift in an optical measurement on a biological sample, such as, for example, the skin of a human forearm.